Aurea

THE CENTER FOR NEUROSCIENCE-BASED MENTAL HEALTH ASSESSMENT AND PREDICTION (NEUROMAP)

15/21 ABCD-USA CONSORTIUM: RESEARCH PROJECT SITE AT LIBR

EFFECTS OF PANDEMIC-RELATED DISRUPTION TO SOCIAL CONNECTEDNESS ON THE BRAIN AND EMOTIONAL WELLBEING IN ADOLESCENTS - PROJECT SUMMARY THE SOCIAL REORIENTATION OF THE ADOLESCENT PERIOD IS ACCOMPANIED BY EXTENSIVE NEURODEVELOPMENTAL CHANGES. TO UNDERSTAND THE NEURODEVELOPMENTAL NETWORKS UNDERLYING RESPONSES TO SOCIAL ENVIRONMENTS AND HOW SOCIAL CONNECTEDNESS INFLUENCES NEURODEVELOPMENT, MANIPULATION OF SOCIAL CONNECTEDNESS AMONG YOUTH IS REQUIRED, WHICH IS IMPOSSIBLE IN A LARGE-SCALE SETTING. IN 2020, THE COVID PANDEMIC HAPPENED, IN THE MIDST OF LONGITUDINAL FOLLOW-UP OF PARTICIPANTS IN THE ADOLESCENT BRAIN COGNITION DEVELOPMENT (ABCD) STUDY, INDUCING DRAMATIC CHANGES TO SOCIAL CONNECTEDNESS IN ADOLESCENTS IN THE STUDY. BECAUSE THE LEVELS OF STAY-AT-HOME RESTRICTION WERE IMPOSED AGNOSTICALLY TO PARTICIPANTS' PRE-PANDEMIC STATUS, THIS BECOMES A NATURALLY OCCURRED EXPERIMENT ON SOCIAL CONNECTEDNESS AMONG ADOLESCENTS. TOGETHER WITH THE COMPREHENSIVE PRE-PANDEMIC ASSESSMENTS, LONGITUDINAL FOLLOW-UP WITH SURVEYS AND GEOLOCATION DATA COLLECTED DURING THE PANDEMIC PERIOD, AND THE RESUMPTION OF MULTIMODAL IMAGING SCANS AND REGULAR ASSESSMENTS RESTARTING DURING, AND CONTINUING AFTER 2021, WE CAN USE LONGITUDINAL ABCD DATA TO CRITICALLY EXAMINE THE RELATIONSHIPS BETWEEN SOCIAL CONNECTEDNESS AND NEURODEVELOPMENT AMONG YOUTH. IN PARTICULAR, WE PROPOSE TO USE ABCD DATA TO INVESTIGATE 1) THE NEUROBIOLOGICAL AND SOCIAL FACTORS (PRE-PANDEMIC) THAT RENDER AN INDIVIDUAL MORE SENSITIVE TO THE DISRUPTION OF SOCIAL CONNECTEDNESS (PERI-PANDEMIC), CONTRIBUTING TO EMOTIONAL TURMOIL DURING AND BEYOND THE PANDEMIC PERIOD; 2) THE MODULATING FACTORS THAT BUFFER/EXACERBATE THE EMOTION RESPONSES DURING A PROLONGED PERIOD OF SOCIAL DISRUPTION (PERI-PANDEMIC); AND 3) THE EXTENT OF DEVIATION IN NEURODEVELOPMENT AFTER THE PANDEMIC (POST-PANDEMIC) IN RELATION TO THE VARYING LEVELS OF SOCIAL DISRUPTIONS IN ABCD PARTICIPANTS DURING THE PANDEMIC. WE WILL PURSUE THESE AIMS BY UTILIZING A NOVEL COMBINATION OF METHODS FROM HIGH-DIMENSIONAL DATA ANALYSIS AND POPULATION INFERENCE, INNOVATIVELY TAILORING THE ANALYTIC STRATEGIES TO AVOID POTENTIAL BIASES AND SPURIOUS ASSOCIATIONS. THE PROPOSED RESEARCH IS OF HIGH PUBLIC HEALTH INTEREST BECAUSE THE IDENTIFIED NEUROBIOLOGICAL MECHANISMS UNDERLYING THE EMOTIONAL RESPONSES TOWARD THE DISRUPTION OF SOCIAL CONNECTEDNESS WILL PROVIDE NOVEL INSIGHTS FOR THERAPEUTICS AND PUBLIC HEALTH INTERVENTIONS IN ADOLESCENTS, DUE TO THE POPULATION-INFORMED ABCD SAMPLE. BY SHARING OUR DEVELOPED TOOLS AND DERIVED SOCIAL VARIABLES FOR THIS RESEARCH PROGRAM, WE WILL IMPACT THE FIELD IMMEDIATELY. THESE NOVEL ANALYTIC TOOLS ENABLE US AND OTHERS TO MORE DEEPLY INVESTIGATE WITH ABCD DATA, NEURODEVELOPMENTAL PROCESSES SPECIFICALLY RELATED TO SOCIAL CONNECTEDNESS. RESULTS CAN INFORM PERI- AND POST-PANDEMIC CLINICAL PRACTICE TO REGAIN AND IMPROVE MENTAL HEALTH IN YOUTH.

KIPIYECIPAKICIIPE "COMING HOME": ESTABLISHING CLINICAL CULTURAL NEUROSCIENCE AS A TOOL FOR UNDERSTANDING THE ROLE OF TRADITIONAL CULTURAL ENGAGEMENT IN MITIGATING SUBSTANCE MISUSE AND DISORDER - PROJECT SUMMARY INEQUITIES IN SUBSTANCE USE DISORDERS (SUDS) AMONG AMERICAN INDIAN (AI) POPULATIONS PERSIST DESPITE DECADES OF AWARENESS AND RESEARCH. ADVANCEMENTS IN HERETOFORE SEPARATE AREAS OF SUD RESEARCH HAVE (1) UNDERSCORED THE IMPORTANCE OF COMMUNITY BASED AND CULTURALLY GROUNDED RESEARCH APPROACHES IN AI POPULATIONS AND (2) SHOWN THE PROMISE OF CLINICAL NEUROSCIENCE'S ROLE IN ADDRESSING SUD. MERGING THESE APPROACHES THROUGH CLINICAL-CULTURAL NEUROSCIENCE IS A MISSING LINK IN THE FIELD WHICH HOLDS LARGE PROMISE FOR ADVANCING BOTH SUD DISPARITIES RESEARCH IN AIS AND UNDERSERVED POPULATIONS, AND THE NEUROSCIENTIFIC UNDERSTANDING OF SUD AND RECOVERY MORE BROADLY. THIS PROPOSAL INTEGRATES COMMUNITY BASED PARTICIPATORY RESEARCH (CBPR) AND CLINICAL-NEUROSCIENCE APPROACHES TO BETTER DELINEATE THE BRAIN PROCESSES THAT ARE IMPORTANT FOR SUD AND THAT ARE IMPACTED BY TRADITIONAL CULTURAL ENGAGEMENT (TCE). THE STUDY AIMS TO LEVERAGE THE LARGE PROMISE OF MULTIMODAL NEUROIMAGING TECHNIQUES AS A METHOD FOR PROBING TCE USING OBJECTIVE MARKERS OF BRAIN STRUCTURE AND FUNCTION. CONCEPTUALIZATION OF TCE WILL BE DONE IN COLLABORATION WITH PARTNERS FROM THE SHAWNEE TRIBE (ST). THIS PARTNERSHIP IS CRITICAL TO THE CURRENT PROJECT AS CULTURE COMPRISES A BROAD CATEGORY OF HUMAN EXPERIENCES COMMON TO A GROUP OF PEOPLE AND IS OFTEN CONFLATED WITH RACE, ETHNICITY, GEOGRAPHIC DISTRIBUTION, AND RELIGION. THIS COMPLEXITY HAS MADE IT DIFFICULT TO PARSE THE INFLUENCE OF CULTURAL FACTORS AND MEANINGFULLY INCORPORATE TCE INTO DISEASE AND TREATMENT MODELS. RECENTLY, ADVANCES IN HEALTH DISPARITIES RESEARCH AMONG AI COMMUNITIES HAVE CONCEPTUALIZED FEATURES OF TCE UNDER THE FRAMEWORK OF SOCIAL DETERMINANTS OF HEALTH (SDH) TO DELINEATE SPECIFIC RISK AND RESILIENCE FACTORS FOR SUD. FURTHERMORE, TCE HAS BEEN SUPPORTED AS PROTECTIVE AGAINST AND AS TREATMENT FOR SUD. THE ST RECOGNIZES THE IMPACT OF HISTORICAL LOSS AND DEGRADATION OF CULTURAL PRACTICES AS A KEY FACTOR IN THE PREVALENCE OF SUD AND IS COMMITTED TO CENTERING COMMUNITY ENGAGEMENT IN DEVELOPING EVIDENCE-BASED INTERVENTION AND PREVENTION EFFORTS INFORMED BY AND INTEGRATING TRADITIONAL CULTURAL KNOWLEDGE AND PRACTICES. KIPIYEECIPSAKICIIPE “COMING HOME” IS A SHAWNEE WORD CHOSEN BY THE ST PARTNERS TO REPRESENT THE EFFORT OF ADVANCING THE SCIENCE OF TCE IN MITIGATING SUD DISPARITIES. A COMMUNITY ADVISORY BOARD OF SHAWNEE ADULTS WILL OVERSEE THE DESIGN, IMPLEMENTATION, AND INTERPRETATION OF THE STUDY. A THREE PHASED APPROACH WILL BE USED TO PROVIDE A MULTI-LEVEL UNDERSTANDING OF TCE AS A PROTECTIVE SDH. PHASE 1 WILL CONSIST OF FOCUS GROUPS AIMED AT REFINING A CONCEPTUALIZATION OF TCE SPECIFIC TO THE ST TO PROVIDE DEEP CONCEPTUAL VALIDITY FOR BEHAVIORAL PROBES AND STIMULI FOR NEURAL PROBES OF TCE. PHASE 2 WILL EXAMINE NEURAL PROBES OF TCE AND NEUROBEHAVIORAL AND COGNITIVE RISK FACTORS FOR SUD ACROSS INDIVIDUALS WITH VARYING DEGREES OF TCE AS DEFINED BY THE CAB. PHASE 3 WILL EXTEND RESULTS TO A SAMPLE OF INDIVIDUAL WITH SUD AND HEALTHY CONTROLS. THIS STUDY WILL PROVIDE A FRAMEWORK FOR STUDYING ANALOGOUS CULTURAL FACTOR ACROSS OTHER RACIAL MINORITY GROUPS TO ADVANCE HEALTH EQUITY.

NEURAL RESPONSE TO INFLAMMATORY CHALLENGE IN MAJOR DEPRESSIVE DISORDER - PROJECT SUMMARY: CHRONIC INFLAMMATION LIKELY UNDERLIES THE PATHOGENESIS OF MAJOR DEPRESSIVE DISORDER (MDD) IN A SIGNIFICANT NUMBER OF CASES BUT WE DO NOT UNDERSTAND WHY THESE INDIVIDUALS GET STUCK IN AN INFLAMMATORY STATE. WE HYPOTHESIZE THAT THIS SUBGROUP OF DEPRESSED PATIENTS HAS A DEFECTIVE HOMEOSTATIC OR REGULATORY RESPONSE TO INFLAMMATORY STIMULI SUCH THAT APPROPRIATE, ACUTE INFLAMMATORY RESPONSES FAIL TO RESOLVE, LEADING TO CHRONIC INFLAMMATION WHICH INCREASES THE RISK FOR (A) DEVELOPING DEPRESSION, (B) ITS RECURRENCE, AND (C) TREATMENT FAILURE. TO TEST THIS HYPOTHESIS, WE PROPOSE CHALLENGING THE IMMUNE SYSTEM OF BOTH MDD SUBJECTS AND HEALTHY CONTROLS (HC) WITH AN INFLAMMATORY STIMULUS (LIPOPOLYSACCHARIDE, LPS) TO INDUCE A HOMEOSTATIC RESPONSE. SPECIFICALLY, 90 MDD AND 90 HC PARTICIPANTS WILL BE RANDOMIZED (2:1) TO LPS (0.8NG/KG) OR SALINE. SERIAL BLOOD DRAWS WILL BE OBTAINED TO QUANTIFY THE PATTERN OF INFLAMMATORY RESPONSE USING SEVERAL INFLAMMATORY MARKERS. AT THE SAME TIME, PARTICIPANTS WILL COMPLETE CLINICAL RATINGS AND UNDERGO A PRE- AND POST-LPS MRI SCAN TO MEASURE HOW THE TRANSIENT INFLAMMATORY RESPONSE AFFECTS THE BRAIN PROCESSING OF INTEROCEPTIVE (BODILY- RELEVANT) STIMULI. PARTICIPANTS WILL ALSO RETURN ONE DAY AND ONE WEEK AFTER LPS/SALINE INFUSION TO COMPLETE IDENTICAL PSYCHOMETRIC MEASURES AND BLOOD DRAWS. THE MDD GROUP, ONLY, WILL ALSO COMPLETE PSYCHOLOGICAL ASSESSMENTS ONCE PER MONTH FOR 6 MONTHS IN ORDER TO DETERMINE WHETHER THE ACUTE RESPONSE TO LPS PREDICTS THE CLINICAL COURSE OF MDD. THE MAIN HYPOTHESES ARE THAT: (1) RELATIVE TO HC, THE MDD GROUP WILL SHOW A GREATER ACUTE INCREASE IN INFLAMMATORY MEDIATORS BUT A BLUNTED ACUTE RESPONSE OF THE NEURAL CIRCUITRY MEDIATING INTEROCEPTIVE PROCESSES (INSULA AND CINGULATE CORTEX) IN THE LPS VS. PLACEBO CONDITION. FOR THE ACUTE OUTCOMES WE FOCUS ON THE CHANGES THAT OCCUR AT THE PEAK OF THE INFLAMMATORY RESPONSE, I.E. 2 HOURS POST-INFUSION. (2). WITHIN THE MDD GROUP, LPS-ASSOCIATED CHANGES IN INTEROCEPTIVE PROCESSING AND FUNCTIONAL CONNECTIVITY WILL BE CORRELATED WITH THE STRENGTH OF THE ACUTE PRO-INFLAMMATORY RESPONSE. (3) THESE ACUTE EFFECTS WILL BE MORE SALIENT IN MDD PARTICIPANTS WITH CHRONIC INFLAMMATION (BASELINE CRP ³3MG/L). THAT IS, RELATIVE TO THE LOW INFLAMMATION MDD GROUP (CRP £1MG/L), THE HIGH INFLAMMATION MDD GROUP WILL DISPLAY A BLUNTED HEMODYNAMIC RESPONSE OF THE INSULA AND CINGULATE DURING INTERNALLY-FOCUSED ATTENTION. IN EXPLORATORY ANALYSES WE WILL ALSO EXAMINE WHETHER THERE IS A SEX BY DIAGNOSIS INTERACTION EFFECT ON INFLAMMATORY AND INSULAR RESPONSE TO LPS AND WHETHER THE ACUTE EFFECTS OF LPS WILL RELATE TO DEPRESSIVE SYMPTOMS OVER THE 6-MONTH FOLLOW-UP. THIS RESEARCH IS INNOVATIVE AND HIGHLY IMPACTFUL BECAUSE IT WILL OPEN UP A NEW PROGRAM OF RESEARCH THAT WILL ALLOW US TO DRAW STRONG CONCLUSIONS ABOUT THE BIOLOGICAL MECHANISMS UNDERLYING THE FAILURE TO RESOLVE INFLAMMATION-RELATED DEPRESSIVE BEHAVIOR. THIS KNOWLEDGE CAN ULTIMATELY BE USED TO DEVELOP NEW BRAIN OR IMMUNE-BASED TREATMENTS TO JUMP-START THE NEURAL CIRCUITRY NORMALLY ENGAGED BY INFLAMMATORY STIMULI, AND TO TARGET THESE INTERVENTIONS AT SPECIFIC PATIENT POPULATIONS.

A NEUROCOMPUTATIONAL ASSAY OF GASTROINTESTINAL INTEROCEPTION IN ANOREXIA NERVOSA - PROJECT SUMMARY GIVEN THAT ANOREXIA NERVOSA (AN) HAS THE HIGHEST MORTALITY RATE OF ANY PSYCHIATRIC ILLNESS AND CURRENT TREATMENTS SHOW LIMITED EFFICACY, THERE IS A CRUCIAL NEED TO BETTER UNDERSTAND THE BRAIN MECHANISMS DRIVING THE PATHOPHYSIOLOGY OF THIS DISORDER. THIS PROPOSAL COMBINES AN EXPERIMENTAL MEDICINE APPROACH FOCUSED ON GASTROINTESTINAL (GI) INTEROCEPTION WITH COMPUTATIONAL MODELING TO PROBE NEURAL CIRCUITS OF INTEROCEPTION AND APPETITE-RELATED GASTRIC PROCESSING IN AN. THE GOAL IS TO IDENTIFY PERCEPTUAL AND NEURAL MARKERS FOR AN AT THE INDIVIDUAL PATIENT LEVEL AND APPLY MACHINE LEARNING METHODS TO TEST CLINICAL OUTCOMES PREDICTION LONGITUDINALLY. SUPPORTED BY OUR PRELIMINARY DATA, THIS PROPOSAL IS BASED ON THE PREMISE THAT THE PATHOPHYSIOLOGY OF AN INCLUDES A COMPUTATIONAL DYSFUNCTION MANIFESTED BY COGNITIVE SUPPRESSION OF THE EXPECTED PRECISION OF AFFERENT INTEROCEPTIVE SIGNALS ASSOCIATED WITH HUNGER, WHICH REDUCES THEIR MOTIVATIONAL INFLUENCE AND FACILITATES MALADAPTIVE AND AVOIDANT EATING BEHAVIORS. WE PROPOSE A CASE-CONTROL STUDY WITH 65 AN AND 65 HEALTHY COMPARISONS WHO WILL UNDERGO EXTENSIVE BASELINE TESTING USING A NOVEL GI INTEROCEPTION PROBE DURING MEASUREMENT OF SYMPTOMS, BEHAVIOR, CIRCUITS, AND PHYSIOLOGY. SENSORY STIMULATION WILL OCCUR DURING THE PREMEAL PERIOD, ANCHORING RESPONSES TO AN ANTICIPATORY CONTEXT WITH HIGH RELEVANCE TO THE DISORDER. THESE INDIVIDUALS WILL BE FOLLOWED FOR 180 DAYS TO EXAMINE CLINICAL OUTCOMES. A COMPUTATIONAL APPROACH WILL EXAMINE THE BASIC HYPOTHESIS THAT AN INDIVIDUALS HAVE LOWER SENSORY PRECISION FOR GI INTEROCEPTION AND THAT THE DEGREE OF SENSORY IMPRECISION IS RELATED TO CLINICAL CHARACTERISTICS. MOREOVER, WE WILL EXAMINE THE RELATIONSHIP OF THIS IMPRECISION TO CIRCUIT AND PHYSIOLOGICAL MEASURES. WE WILL THEN APPLY MACHINE LEARNING APPROACHES TO THESE NEUROPHYSIOLOGICAL AND PERCEPTUAL MEASURES TO LONGITUDINALLY TEST THE PREDICTION OF CLINICAL OUTCOMES. ACHIEVING THE AIMS OF THIS PROJECT WILL PROVIDE UNIQUE INSIGHTS INTO THE PATHOPHYSIOLOGY OF AN BY ARBITRATING WHETHER AN IS A CONSEQUENCE OF “TOP-DOWN” OR “BOTTOM-UP” DYSREGULATION IN THE NERVOUS SYSTEM, WHICH COULD TRANSFORM OUR UNDERSTANDING OF HOW INTRINSIC INTEROCEPTIVE DISTURBANCES LEAD TO AN. PRAGMATICALLY, IT WILL RESULT IN NEW TECHNOLOGIES FOR IDENTIFYING INTEROCEPTIVE DYSFUNCTION AT THE INDIVIDUAL LEVEL, ALLOWING PSYCHIATRY TO DEVELOP DIAGNOSTIC AND PREDICTIVE BIOMARKERS OF AN. THUS THE NEUROCOMPUTATIONAL ASSAY OF GASTROINTESTINAL INTEROCEPTION IN AN COULD BE USED TO DEVELOP LOW-COST, SCALABLE, AND OBJECTIVE TOOLS FOR IDENTIFYING DYSFUNCTION IN INDIVIDUAL PATIENTS, TO FACILITATE NEUROBIOLOGICALLY-BASED DEFINITIONS OF RECOVERY, AND TO PREDICT THE RISK OF RELAPSE FOLLOWING TREATMENT. FINALLY, THIS PROPOSAL LAYS THE GROUNDWORK FOR THE FUTURE DEVELOPMENT OF PRECISION PSYCHIATRIC INTERVENTIONS SUCH AS PERCEPTUAL RETRAINING THERAPIES TO TARGET (AND RECALIBRATE) ABNORMAL BRAIN- BODY INTERACTIONS.

EMOTION REGULATION TRAINING FOR TREATING WARFIGHTERS WITH COMBAT RELATED PTSD USING REAL-TIME FMRI AND EEG-ASSIGNED NEUROFEEDBACK

PLASTICITY OF AVERSIVE SALIENCE IN OPIOID USE DISORDER - ABSTRACT/PROJECT SUMMARY NOT-DA-20-012 GIVEN THAT DEATHS LINKED TO OPIOID ADDICTION ARE AT AN ALL-TIME HIGH IN THE UNITED STATES, THERE IS A CRUCIAL NEED TO UNDERSTAND BRAIN MECHANISMS IMPEDING VERSUS PROMOTING RECOVERY, A PROCESS MARKED BY PROLONGED ABSTINENCE AND USE OF INTERNAL/EXTERNAL RESOURCES TO RESOLVE DRUG PROBLEMS. THE BROAD AIMS OF THIS PROPOSAL ARE TO UNDERSTAND HOW BRAIN CIRCUITRY IMPLICATED IN THE SALIENCE OF AVERSIVE INTERNAL (BODILY SIGNALS) AND EXTERNAL (STRESSFUL, LOSS) STIMULI TRACKS RECOVERY WITHIN AND ACROSS INDIVIDUALS WITH OPIOID ADDICTION TO (1) INFORM FUTURE TARGETS FOR INTERVENTION (E.G., BRAIN NEUROFEEDBACK); AND (2) AID THE DEVELOPMENT OF INDIVIDUALIZED TREATMENT TO REDUCE DRUG-RELATED DEATHS. WITHIN THREE MONTHS OF TREATMENT, 50% OF SUBSTANCE USERS RELAPSE, TAKING DRUGS TO AVOID AVERSIVE BODILY STATES LINKED TO CRAVING, WITHDRAWAL, AND STRESS. OUR PRELIMINARY DATA SUGGEST THAT OPIOID USERS SHOW GREATER NEGATIVE AFFECT, HIGHER INTENSITY OF INTERNAL SENSATIONS, AND FASTER PAIN REACTIVITY THAN HEALTHY CONTROLS, PAIRED WITH LOWER SALIENCE- RELEVANT BRAIN RESPONSES DURING ATTENTION TO BODILY SIGNALS AND ANTICIPATION OF MONETARY LOSSES HOWEVER, IT IS UNCLEAR WHETHER AVERSIVE SALIENCE-RELATED BRAIN CIRCUITRY IMPROVES AND TRACKS RECOVERY DURING THE VULNERABLE FIRST THREE MONTHS DURING TREATMENT. THE SPECIFIC AIMS OF THIS PROPOSAL TEST HOW SALIENCE-BASED BRAIN CIRCUITRY DIFFERS BETWEEN 200 TREATMENT-SEEKING INDIVIDUALS WITH OPIOID USE DISORDER AND 50 HEALTHY INDIVIDUALS AT FOUR TIMEPOINTS DURING EARLY OPIOID RECOVERY (2 WEEKS AND 1, 2, AND 3 MONTHS), IDENTIFYING WHAT SELF-REPORT, BEHAVIORAL, AND BRAIN VARIABLES CAN BE USED TO IDENTIFY OPIOID USERS AT HIGH RISK FOR RELAPSE VERSUS THOSE WHO MAINTAIN ABSTINENCE. FUNCTIONAL MAGNETIC RESONANCE IMAGING (FMRI) PARADIGMS INVOLVING BODILY AWARENESS, MONETARY WIN/LOSS, AND STRESS/DRUG CUES, SUBSTANCE USE ASSESSMENTS, AND NIDA SELF-REPORT/BEHAVIORAL PHENOTYPING BATTERIES WILL BE COLLECTED AT EACH TIMEPOINT. ONCE THE PROPOSED AIMS ARE COMPLETED, THE FINDINGS FROM THIS DATASET WILL BE EVALUATED TO DETERMINE WHETHER THESE PREDICTION METRICS CAN BE VALIDATED IN ADDITIONAL TREATMENT-SEEKING SAMPLES.

AN APPROACH-AVOIDANCE, COMPUTATIONAL FRAMEWORK FOR PREDICTING BEHAVIORAL THERAPY OUTCOME IN ANXIETY AND DEPRESSION

INFLAMMATORY TRANSCRIPTS, GENES AND POSITIVE VALENCE SYSTEM FUNCTION IN ANHEDONIA

IDENTIFYING AND QUANTIFYING GENETIC EFFECTS ON NEURODEVELOPMENTAL TRAJECTORIES IN ADOLESCENTS

THEORY OF MIND SOFTWARE FOR AUTISM AND OTHER COMMUNICATION DISORDERS

PROCESSES AND CIRCUITRY UNDERLYING THREAT SENSITIVITY AS A TREATMENT TARGET FOR COMORBID ANXIETY AND DEPRESSION - PROJECT SUMMARY NEARLY HALF OF INDIVIDUALS WITH MAJOR DEPRESSIVE DISORDER (MDD) HAVE A COMORBID ANXIETY DISORDER (AD), WHICH IS ASSOCIATED WITH TREATMENT RESISTANCE, MORBIDITY, AND MORTALITY. YET, THE UNDERLYING PROCESS DYSFUNCTIONS THAT CHARACTERIZE COMORBID AD AND MDD (AD-MDD) ARE POORLY UNDERSTOOD. THE PREMISE OF THIS PROPOSAL IS THAT EXAGGERATED THREAT SENSITIVITY IN GENERAL, AND POTENTIAL THREAT VS ACUTE THREAT IN PARTICULAR DIFFERENTIATES AD- MDD FROM MDD. THIS PROJECT BUILDS ON OUR PILOT DATA SHOWING THAT PEOPLE WITH AD-MDD HAVE EXAGGERATED THREAT SENSITIVITY COMPARED TO THOSE WITH MDD ACROSS SEVERAL LEVELS (SELF-REPORT, STARTLE ELECTROMYOGRAM [EMG], FUNCTIONAL MAGNETIC RESONANCE IMAGING [FMRI] AND BEHAVIORAL), AND AIMS TO DELINEATE AND QUANTIFY THE NEURAL CIRCUIT DYSFUNCTIONS UNDERLYING THREAT SENSITIVITY (POTENTIAL AND ACUTE THREAT) IN AD-MDD RELATIVE TO MDD AND AD. IF CONFIRMED, THE PROPOSED STUDIES WOULD PROVIDE BEHAVIORAL, NEURAL, AND ELECTROPHYSIOLOGICAL PROCESSES THAT CAN BE USED FOR BOTH QUANTITATIVE SEVERITY ASSESSMENT AND AS A TREATMENT TARGET FOR AD-MDD. WHEREAS BOTH AD-MDD AND MDD INDIVIDUALS SHOW BLUNTED REWARD AND INTEROCEPTIVE/SALIENCE PROCESSING, ONLY AD-MDD SHOW EXAGGERATED THREAT SENSITIVITY. HOWEVER, THE NEURAL BASIS FOR THREAT SENSITIVITY IS COMPLEX AND CONSISTS OF BOTH POTENTIAL THREAT (PT; “ANXIETY”) AND ACUTE THREAT (AT; “FEAR”) RELATED PROCESSES, WHICH INVOLVE DIFFERENT CIRCUITS, THAT HAVE NOT BEEN EXAMINED IN AD-MDD. THIS PROPOSAL FOCUSES ON THIS CRUCIAL GAP TO BETTER DELINEATE THE NEURAL CIRCUITRY. BENZODIAZEPINES ARE COMMON ANXIOLYTICS WHICH ARE GABAERGIC AGONISTS AND REDUCE PT RATHER THAN AT. WE PROPOSE TO USE THE BENZODIAZEPINE LORAZEPAM, AS AN ACUTE PHARMACOLOGICAL PROBE TO CAUSALLY STUDY THREAT CIRCUITRY AND DELINEATE NEURAL MECHANISMS CONTRIBUTING TO AD-MDD, MDD AND AD. THIS PROPOSAL'S AIMS FOCUS ON: (1) PROBING DIFFERENCES IN PT AND AT AT MULTIPLE LEVELS OF ANALYSIS BETWEEN AD-MDD, MDD AND AD; AND (2) DETERMINING HOW PHARMACOLOGICAL MANIPULATION TARGETING PT DIFFERS IN ITS ACUTE NEUROLOGICAL, ELECTROPHYSIOLOGICAL AND BEHAVIORAL EFFECTS ON AD-MDD VS MDD VS AD. WE PROPOSE: (1) THE INTERACTION OF INCREASED THREAT SENSITIVITY AND REWARD/SALIENCE BLUNTING CONTRIBUTES TO UNIQUE NEURAL AND BEHAVIORAL RESPONSES THAT ARE ASSOCIATED WITH GREATER DISEASE BURDEN FOR AD-MDD THAN MDD; AND (2) THIS SENSITIVITY IN AD-MDD IS MECHANISTICALLY RELATED TO SPECIFIC NEURAL ACTIVATION CHANGES IN TARGETABLE CIRCUITS ASSOCIATED WITH PT. THIS MECHANISTIC R01 USES A BENZODIAZEPINE WITHIN AN EXPERIMENTAL MEDICINE MODEL APPROACH TO CAUSALLY MODULATE THE THREAT PROCESSING SYSTEM AND ASSOCIATED CIRCUITS IN AD- MDD (N=55), MDD (N=55), AND AD (N=55). IN A CROSSOVER DESIGN, PARTICIPANTS WILL RECEIVE A SINGLE 1MG DOSE OF LORAZEPAM AND PLACEBO AND COMPLETE THREAT TASKS THAT DELINEATE PT/AT DURING EYEBLINK STARTLE EMG (AIM 1/3) AND FMRI (AIM 2/3). THE ULTIMATE GOAL OF THIS RESEARCH IS TO ESTABLISH TREATMENT TARGETS FOR AD-MDD FOR NOVEL INTERVENTIONS AND PROVIDE EVIDENCE FOR THE SEPARATION OF MDD AND AD-MDD IN FUTURE CLINICAL TRIALS.

ADVANCED PLACEMENT FEE PAYMENT PROGRAM - INCENTIVE PROGRAM

SOFTWARE TO ENRICH THE NOUN LEXICONS AND LEXICAL LEARNING OF CHILDREN WITH AUTISM

NEURAL BASIS OF MEAL RELATED INTEROCEPTIVE DYSFUNCTION IN ANOREXIA NERVOSA

APPROACH-AVOIDANCE CONFLICT-A MULTI-LEVEL PREDICTOR FOR EXPOSURE THERAPY RESPONSE

THE NEURAL BASES OF PATHOLOGICAL FOOD PERCEPTION AND CHOICE IN MAJOR DEPRESSION

NEUROIMAGING ABNORMALITIES IN MAJOR DEPRESSIVE DISORDER: EFFECT OF INFLAMMATION

INVESTIGATING FLOTATION-REST AS A NOVEL TECHNIQUE FOR REDUCING ANXIETY AND DEPRESSION

DEVELOPING AND EVALUATING A POSITIVE VALENCE TREATMENT FOR ALCOHOL USE DISORDER WITH ANXIETY OR DEPRESSION - PROJECT SUMMARY ONLY 20-30% OF INDIVIDUALS WITH ALCOHOL USE DISORDER (AUD) EXHIBIT LONG-TERM BENEFITS WITH LEADING PHARMACOLOGIC (E.G., ACAMPROSATE, NALTREXONE) AND BEHAVIORAL THERAPIES (E.G., COGNITIVE BEHAVIORAL THERAPY, CONTINGENCY MANAGEMENT). NEARLY HALF OF INDIVIDUALS SEEKING TREATMENT FOR AUD EXPERIENCE CLINICALLY SIGNIFICANT ANXIETY AND DEPRESSION SYMPTOMS (ANX/DEP), WHICH RELATE TO WORSE LONG-TERM OUTCOMES. POSITIVE VALENCE SYSTEM (PVS) DYSFUNCTION IS A COMMON AND PERNICIOUS FEATURE OF BOTH AUD AND ANX/DEP THAT IS PREDICTIVE OF POOR FUNCTIONING AND PROGNOSIS. ALTHOUGH PVS DYSFUNCTION REPRESENTS A SHARED PATHOPHYSIOLOGIC MECHANISM ACROSS AUD AND ANX/DEP, IT IS NOT SUFFICIENTLY TARGETED BY EXISTING TREATMENTS. OUR TEAM DEVELOPED A BEHAVIORAL INTERVENTION, AMPLIFICATION OF POSITIVITY (AMP), TO ENHANCE PVS FUNCTION THROUGH INCREASING EXPOSURE AND RESPONSIVITY TO NON-DRUG REWARDS. IN OUR PREVIOUS WORK, AMP WAS FOUND TO INCREASE POSITIVE VALENCE OUTCOMES (E.G., POSITIVE AFFECT, SOCIAL CONNECTEDNESS, LIFE SATISFACTION), ENHANCE REACTIVITY OF PVS NEURAL CIRCUITS (I.E., STRIATAL RESPONSE TO SOCIAL REWARD), AND DECREASE NEGATIVE VALENCE OUTCOMES AND SYMPTOMS FOR INDIVIDUALS WITH ANX/DEP. WE HAVE BEGUN TO MODIFY THIS INTERVENTION FOR THE TREATMENT OF CO-OCCURRING AUD AND ANX/DEP (AMP-A), COMPLETING AN INITIAL PILOT FEASIBILITY STUDY. FOR THE PROPOSED STUDY, WE WILL FURTHER DEVELOP AND REFINE AMP-A BASED UPON QUALITATIVE AND QUANTITATIVE FEEDBACK FROM CLINICIANS AND PARTICIPANTS AND COMPLETE A PILOT STUDY OF THE PROTOCOL WITH EIGHT INDIVIDUALS DIAGNOSED WITH AUD AND REPORTING CLINICALLY ELEVATED ANX/DEP SYMPTOMS - FURTHER REFINING THE PROTOCOL BASED ON FEEDBACK FROM THIS PILOT. WE WILL THEN RECRUIT 60 INDIVIDUALS WITH AUD+ANX/DEP AND RANDOMIZE THEM TO COMPLETE AMP-A OR COGNITIVE BEHAVIORAL THERAPY (CBT) – A FIRST-LINE TREATMENT FOR AUD THAT HAS SMALL EFFECTS ON THE PVS. ALL PARTICIPANTS WILL COMPLETE CLINICAL AND SELF-REPORT MEASURES BEFORE, DURING AND AFTER THERAPY AND AT 3-MONTH FOLLOW-UP. THIS PROJECT WILL ACCOMPLISH THE FOLLOWING AIMS: (1) FURTHER DEVELOP AND REFINE AMP-A TO OPTIMIZE ITS ACCEPTABILITY AND POTENTIAL CLINICAL UTILITY; (2) DETERMINE THE EFFECTS OF AMP-A COMPARED TO CBT ON THE PVS, AS MEASURED BY SELF-REPORT OF POSITIVE AFFECT, SOCIAL CONNECTEDNESS, WELL-BEING, AND REWARD PROCESSING; (3) DETERMINE WHETHER INCREASES IN PVS FUNCTION ARE ASSOCIATED WITH GREATER CLINICAL IMPROVEMENT OF ALCOHOL USE, ANXIETY, AND DEPRESSION. RESULTS WILL HAVE IMPORTANT IMPLICATIONS FOR THE TREATMENT OF AUD AND CO-OCCURRING ANXIETY OR DEPRESSION BY DETERMINING THE UTILITY OF DIRECTLY TARGETING THE PVS, WHICH WILL PAVE THE WAY FOR FUTURE RESEARCH SEEKING TO REMEDIATE THE HARMFUL EFFECTS OF THESE CONDITIONS.

NEUROSCIENTIFIC EXPLORATION OF CULTURAL PROTECTIVE FACTORS IN AMERICAN INDIANS - PROJECT SUMMARY AMERICAN INDIAN (AI) POPULATIONS HAVE HAD THE LARGEST INCREASE IN SUICIDE RATES OF ANY ETHNIC GROUP IN THAT PAST DECADE AND HAVE HIGH RATES OF MENTAL HEALTH CONCERNS SUCH AS POST-TRAUMATIC STRESS, SUBSTANCE USE, ANXIETY, AND MOOD DISORDERS. HOWEVER, PREVIOUS RESEARCH AND PRELIMINARY ANALYSES DEMONSTRATED THAT AIS ACTUALLY DISPLAY LOWER LEVELS OF MENTAL HEALTH CONCERNS THAN BROADER POPULATIONS WHEN ACCOUNTING FOR INCREASED LEVELS OF RISK FACTORS, (E.G., TRAUMA EXPOSURE). EXTANT LITERATURE INDICATES THAT FACTORS ASSOCIATED WITH AI CULTURE ARE PROTECTIVE AGAINST POOR MENTAL HEALTH. YET, LITTLE IS KNOWN ABOUT HOW CULTURAL FACTORS (E.G., ENCULTURATION, SOCIAL SUPPORT) PLAY A PROTECTIVE ROLE. THERE ARE NO PUBLISHED STUDIES EXAMINING NEURAL UNDERPINNINGS OF THE PROTECTIVE ROLE OF AI CULTURAL FACTORS. FILLING THIS GAP IS A CRITICAL STEP IN SUPPORTING AN EXPERIMENTAL THERAPEUTICS APPROACH TO DEVELOPING CULTURALLY INFORMED PREVENTION AND INTERVENTION EFFORTS. COGNITIVE CONTROL IS A NEUROCOGNITIVE FUNCTION THAT IS IMPLICATED ACROSS NUMEROUS PSYCHIATRIC DISORDERS, CAN BE ASSESSED WITH VALIDATED BEHAVIORAL AND NEUROIMAGING TASKS, AND HAS BEEN WELL-DELINEATED IN REGARD TO UNDERLYING NEURAL CIRCUITRY. THE AIMS OF THE PROPOSAL ARE TO (A) DETERMINE WHETHER CULTURAL PROTECTIVE FACTORS RELATE TO BEHAVIORAL AND NEURAL INDICATORS OF COGNITIVE CONTROL, AS MEASURED DURING ELECTROENCEPHALOGRAPHY AND FUNCTIONAL MAGNETIC RESONANCE IMAGING AND (B) DEVELOP AN EXPERIMENTAL, CULTURAL IDENTIFICATION PARADIGM TO SERVE AS THE BASIS FOR FUTURE CULTURALLY-INFORMED NEUROSCIENTIFIC RESEARCH AND INTERVENTION/PREVENTION EFFORTS. A COMMUNITY BASED PARTICIPATORY RESEARCH (CBPR) FRAMEWORK WILL BE USED TO RECRUIT PARTICIPANTS WHO HAVE COMPLETED MULTIMODAL NEURAL AND BEHAVIORAL INDICATORS OF COGNITIVE CONTROL, CLINICAL INTERVIEWS, SELF-REPORT MEASURES OF PSYCHOPATHOLOGY SYMPTOMS AND GLOBAL FUNCTIONING AS PART OF A PREVIOUS STUDY. THEY WILL COMPLETE SELF-REPORT MEASURES OF ENCULTURATION, SOCIAL SUPPORT, GLOBAL FUNCTIONING AND A CULTURAL ENHANCEMENT INDUCTION PARADIGM DEVELOPED USING A CBPR FRAMEWORK. THESE DATA WILL PROVIDE AN ESSENTIAL FOUNDATION FOR DEVELOPING CULTURALLY INFORMED, EVIDENCE-BASED INTERVENTION AND PREVENTION EFFORTS AIMED AT REDUCING THE MENTAL HEALTH DISPARITIES AMONG AIS. THE PROPOSED TRAINING PLAN WILL EXPAND DR. WHITE EXPERTISE IN NEUROSCIENTIFIC MECHANISMS OF COGNITIVE CONTROL THROUGH MENTORSHIP, COURSEWORK, AND HANDS-ON TRAINING IN ADVANCED STATISTICAL METHODS, MULTIMODAL (EEG/FMRI) NEUROIMAGING, CLINICAL NEUROSCIENCE, AND CULTURALLY INFORMED RESEARCH. HE HAS ASSEMBLED A TEAM OF MENTORS WELL SUITED TO PROVIDE THE REQUIRED DIVERSITY OF EXPERTISE HE NEEDS TO ACHIEVE INDEPENDENCE. DR. MARTIN PAULUS WILL PROVIDE EXPERTISE NEUROIMAGING AND ADVANCED DATA ANALYTIC EXPERTISE. DR. AUPPERLE WILL BRING EXTENSIVE EXPERIENCE RELATED TO NEUROIMAGING AND CLINICALLY RELEVANT NEUROSCIENCE APPROACHES. DR. LOWE WILL PROVIDE EXPERTISE AND EXPERIENCES IN AI CULTURALLY INFORMED RESEARCH. THE TRAINING AND ASSOCIATED RESEARCH WILL BE CONDUCTED AT LIBR, A STATE-OF-THE-ART INSTITUTE DEDICATED TO NEUROIMAGING RESEARCH AIMED AT DEVELOPING MORE EFFECTIVE TREATMENTS FOR NEUROPSYCHIATRIC DISORDERS.

PARSING MECHANISTIC RELATIONSHIPS BETWEEN CIRCUITS AND NEGATIVE VALENCE SYSTEM BEHAVIORS IN TREATMENT-RESISTANT DEPRESSION WITH ULTRASOUND NEUROMODULATION - PROJECT SUMMARY APPROXIMATELY ONE THIRD OF INDIVIDUALS WITH DEPRESSION ARE CONSIDERED TREATMENT-RESISTANT (TRD) AND EXHIBIT SYMPTOMS ANCHORED IN ABNORMALITIES OF RDOC NEGATIVE VALENCE SYSTEMS BEHAVIORAL PROCESSES. FOR EXAMPLE, ANHEDONIA AND RUMINATION CONTRIBUTE TO SIGNIFICANT IMPAIRMENT IN DAILY FUNCTIONING, HIGH RELAPSE RATES, AND A STAGGERING GLOBAL TOLL OF OVER 700,000 ANNUAL SUICIDES. ONE REASON FOR INADEQUATE TREATMENT RESPONSE IS OUR LIMITED UNDERSTANDING OF CAUSAL MECHANISMS LINKING BRAIN CIRCUIT FUNCTION TO NEGATIVE VALENCE BEHAVIOR ABNOR- MALITIES, WHICH IMPEDES THE DEVELOPMENT OF PRECISION NEUROMODULATION TREATMENTS. WE PROPOSE TO ADDRESS THIS PROBLEM BY USING LOW-INTENSITY FOCUSED ULTRASOUND (LIFU), WHICH CAN NONINVASIVELY AND REVERSIBLY MODULATE DEEP BRAIN CIRCUITS, TO DETERMINE THE MECHANISTIC RELATIONSHIP BETWEEN CORTICO-SUBCORTICAL CIRCUITS AND DISTINCT NEGATIVE VALENCE SYSTEM BEHAVIORS INCLUDING REWARD PROCESSES AND RUMINATION. SUBSTANTIAL PRELIMINARY EVI- DENCE SUGGESTS THAT ABERRANT CONNECTIVITY BETWEEN THE THALAMUS AND ORBITOFRONTAL (OFC) OR ANTERIOR CINGULATE (ACC) CORTICES IN THE RIGHT HEMISPHERE CONTRIBUTE TO DISTINCT DEPRESSION-RELATED RDOC NEGATIVE VALENCE SYS- TEM BEHAVIORAL CHANGES. IN A PRELIMINARY CLINICAL TRIAL, WHICH RECEIVED A NON-SIGNIFICANT RISK DETERMINATION BY THE FDA (NCT05697172) WE OBSERVED SAFE MODULATION OF DEEP WHITE MATTER TRACTS USING LIFU. WE NOW PROPOSE TO EMPLOY ADVANCED STRUCTURAL IMAGING TECHNIQUES TO TAILOR MODULATION TARGETS TO EACH PATIENT'S UNIQUE ANATOMY. OUR STUDY WILL INVOLVE 120 TRD PARTICIPANTS WHO WILL RECEIVE LIFU AND SHAM STIMULATION TO INDIVIDUALLY-DEFINED WHITE MATTER TRACTS CONNECTING THALAMUS WITH EITHER OFC (N=60) OR ACC (N=60). WE WILL MEASURE RESTING-STATE FUNCTIONAL MAGNETIC RESONANCE IMAGING (FMRI) CHANGES, AND CHANGES IN TWO BEHAVIORAL MODELS UNDERLYING NEGATIVE VALENCE MANIFESTATIONS (MONETARY INCENTIVE DELAY AND INDUCED RUMINATION TASKS). OUR HYPOTHESIS IS THAT THALAMO-OFC AND THALAMO-ACC HYPERCONNECTIVITY, HISTORICALLY TARGETED IN NEUROMODULATION TECHNIQUES USEFUL IN TRD, CONTRIBUTES TO DISTORTIONS IN DISTINCT BEHAVIORAL COMPONENTS OF THE NEGATIVE VALENCE SYSTEM. THIS PROPOSAL THUS HAS THE FOLLOWING SPECIFIC AIMS: IN AIM 1, WE WILL DETERMINE THE ANATOMICAL SPECIFICITY OF LIFU WHEN APPLIED TO THALAMO-OFC AND THALAMO-ACC WHITE MATTER TRACTS. WE PREDICT THAT LIFU WILL LEAD TO RE- DUCED FUNCTIONAL CONNECTIVITY IN THE SPECIFIC CORTICAL REGIONS REACHED BY THE MODULATED WHITE MATTER BUNDLES. IN AIM 2, WE WILL CORRELATE CONNECTIVITY BETWEEN THALAMUS AND OFC OR ACC, WITH FUNCTIONAL FEATURES OF DISTINCT BEHAVIORS PERTAINING TO THE RDOC NEGATIVE VALENCE. EXPLORATORY AIM 3 WILL ESTABLISH BEHAVIORAL CORRELATES OF SUCH NEURAL CHANGES. IF SUCCESSFUL, THE PRESENT PROPOSAL WILL CONTRIBUTE TO UNDERSTANDING CLINICALLY MEANINGFUL BRAIN-BEHAVIOR MECHANISTIC RELATIONSHIPS BY PARSING THALAMO-PREFRONTAL CIRCUITS AND RDOC NEGATIVE VALENCE SYSTEM BEHAVIORS. IN TURN, SUCH DEFINITION OF TARGETS WITH A CAUSAL ROLE IN ABNORMAL BEHAVIOR PROCESSES, COULD INFORM PRECISION THERAPEUTIC NEUROMODULATION IN A PSYCHIATRIC POPULATION IN UTTER NEED OF INNOVATIVE TREATMENTS. 1

IN VIVO INFLAMMATORY CHALLENGE TO ELUCIDATE THE ROLE OF THE TOLL-LIKE RECEPTOR 4 PATHWAY IN DEPRESSION - PROJECT SUMMARY APPROXIMATELY 1/3 OF INDIVIDUALS WITH MAJOR DEPRESSIVE DISORDER (MDD) DISPLAY INFLAMMATION THAT IS BELIEVED TO PLAY A CAUSAL ROLE IN THE DISORDER, BUT THE PRECISE MECHANISMS ARE NOT UNDERSTOOD. EXPERIMENTAL ENDOTOXEMIA STUDIES IN HEALTHY INDIVIDUALS HAVE SHOWN BEHAVIORAL, IMMUNOLOGICAL, AND PHYSIOLOGICAL CHANGES LEADING TO A TRANSIENT DEPRESSIVE-LIKE STATE THAT RESOLVES 4-5 HOURS AFTER ADMINISTRATION OF LIPOPOLYSACCHARIDE (LPS). WHILE INFORMATIVE, THESE STUDIES CANNOT REVEAL PUTATIVE, ABERRANT INFLAMMATORY AND REGULATORY MECHANISMS IN MDD. HENCE, A MECHANISTIC APPROACH IS REQUIRED TO PINPOINT WHICH IMMUNOREGULATORY MECHANISMS ARE DEFECTIVE IN MDD. THIS PROPOSAL WILL LEVERAGE AN EXPERIMENTAL MEDICINE STUDY INVOLVING ACUTE ADMINISTRATION OF LPS OR SALINE TO INDIVIDUALS WITH MDD AND HEALTHY CONTROLS (HC) TO IDENTIFY DEPRESSION-RELEVANT CHANGES IN THE TLR4 PATHWAY AND ITS REGULATION BY MICRORIBONUCLEIC ACIDS (MIRNAS) IN BOTH THE BLOOD AND THE BRAIN. THE CENTRAL HYPOTHESIS IS THAT TLR4 SIGNALING IS SENSITIZED IN MDD BY A HISTORY OF EXPOSURE TO EXOGENOUS (E.G. PATHOGENS, LPS FROM LEAKY GUT) AND/OR ENDOGENOUS (E.G. CHRONIC STRESS) LIGANDS, AND THUS, TLR4-MEDIATED INFLAMMATORY AND REGULATORY MECHANISMS ARE IMPAIRED IN MDD SUBJECTS COMPARED TO HC. TLR4 DETECTS PATHOGEN- AND DAMAGE-ASSOCIATED MOLECULAR PATTERNS (PAMPS AND DAMPS) FOR PRODUCTION OF INFLAMMATORY CYTOKINES, SUCH AS INTERLEUKIN 6 (IL-6) AND TUMOR NECROSIS FACTOR (TNF), WHICH ARE ELEVATED IN SOME INDIVIDUALS WITH MDD. WHILST PAMPS, LIKE LPS PLAY A ROLE IN THE PATHOGENESIS OF MDD, STRESS-ASSOCIATED PRODUCTION OF DAMPS MAY ALSO ACTIVATE TLR4. DESPITE THE THEORETICAL IMPORTANCE OF THE TLR4 PATHWAY, THE EVIDENCE BASE IS CURRENTLY SMALL, THE EXTANT CLINICAL DATA ARE CROSS-SECTIONALLY DERIVED, AND TLR4 DOWNSTREAM SIGNALING HAS NOT BEEN ASSESSED DESPITE ABERRANT EXPRESSION OF TLR4-RESPONSIVE MIRNAS IN MDD. THESE MIRNAS CAN BE ISOLATED FROM EXTRACELLULAR VESICLES (EVS) THAT CROSS THE BLOOD BRAIN BARRIER, THUS, ISOLATING EVS OF GLIAL ORIGIN WILL PROVIDE A READOUT OF CNS-ASSOCIATED TLR4 REGULATION IN MDD. OUR PRELIMINARY DATA SUGGEST THAT THE INFLAMMATORY CYTOKINES, IL-6 AND TNF, AS WELL AS TLR4 ARE INCREASED IN MDD COMPARED TO HC IN RESPONSE TO LPS. THE K99 PHASE WILL IDENTIFY PERIPHERAL AND CENTRAL TLR4-MEDIATED IMMUNE SIGNALING MECHANISMS IN MDD WITH THE USE OF HIGH-SENSITIVITY, IMMUNOASSAY DETECTION TO IDENTIFY CHANGES IN CYTOKINE EXPRESSION AND TLR4 PATHWAY PROTEINS AND SUPPORT THE PI’S TRAINING IN FLOW CYTOMETRY, MIRNA EXTRACTION, ASTROCYTE-ENRICHED EV (AEEV) ISOLATION, AND RNA-SEQ. THE R00 PHASE WILL IDENTIFY PERIPHERAL AND CENTRAL TLR4-MEDIATED REGULATORY MECHANISMS IN MDD WITH THE USE OF NEXT GENERATION SEQUENCING TO IDENTIFY MIRNAS DYSREGULATED IN MDD AND WILL PROVIDE SUPPORT FOR TRANSITION TO AN INDEPENDENT INVESTIGATOR SPECIALIZING IN CNS-DEPENDENT TLR4- INFLAMMATORY MECHANISMS IN DEPRESSION. THE ABILITY TO DELINEATE TLR4-MEDIATED PERIPHERAL AND CNS IMMUNOREGULATORY RESPONSES WITH CUTTING EDGE TECHNIQUES, STILL NOVEL TO THE FIELD OF PSYCHIATRY, WILL MOVE US ONE STEP CLOSER TO UNDERSTANDING THE MECHANISMS UNDERLYING INFLAMMATION-ASSOCIATED DEPRESSION.

ACUTE MODULATION OF NEURAL CIRCUITRY REGULATING IMMUNE FUNCTION IN DEPRESSION

INTEROCEPTIVE MECHANISMS OF BODY IMAGE DISTURBANCE IN ANOREXIA NERVOSA - PROJECT ABSTRACT/SUMMARY DR. EMILY CHOQUETTE IS APPLYING FOR THE MENTORED PATIENT-ORIENTED CAREER DEVELOPMENT AWARD (K23) TO SUPPORT HER GROWTH AS AN INDEPENDENT RESEARCHER FOCUSING ON UNDERSTANDING THE PATHOPHYSIOLOGY OF BODY IMAGE DISTURBANCE (BID). BID IS A KEY DIAGNOSTIC FEATURE OF AN THAT IS ASSOCIATED WITH POOR OUTCOMES INCLUDING RELAPSE FOLLOWING HOSPITAL DISCHARGE. PERCEPTUAL BID IS A COMPLEX PROCESS INVOLVING THE INTEGRATION OF BODILY SIGNALS (INTEROCEPTION), AFFERENT VISUAL STIMULI, AND MENTAL REPRESENTATIONS OF ONE'S BODY. SPECIFICALLY, THERE IS EVIDENCE THAT BID IS RELATED TO AN IMBALANCE OF SENSITIVITY TO INTEROCEPTIVE AND EXTEROCEPTIVE SIGNALING IN AN, WHICH FACILITATES SELF-OBJECTIFICATION (SEEING ONE'S BODY AS AN OBJECT) AND RESULTS IN AN INACCURATE REPRESENTATION OF THE BODY (I.E., PERCEIVING ONE'S BODY AS LARGER THAN ITS TRUE SIZE). THE PROPOSED STUDY WILL BE THE FIRST TO SYSTEMATICALLY EXAMINE ASSOCIATIONS BETWEEN BID AND INTEROCEPTION USING SEVERAL LEVELS OF ANALYSIS (I.E., SELF- REPORT AND BEHAVIORAL ASSAYS) COMBINED WITH PERTURBATIONS OF INTEROCEPTIVE (I.E., REDUCED ENVIRONMENTAL STIMULATION THERAPY VIA FLOATATION) AND COGNITIVE (I.E., ACCEPTANCE BASED COGNITIVE PRINCIPLES) PROCESSING TO EXAMINE THE CAUSAL ROLE OF INTEROCEPTION ON PERCEPTUAL BID. THE AIMS OF THE CURRENT PROJECT ARE TO (1) EXAMINE HOW A COGNITIVE VERSUS INTEROCEPTIVE INTERVENTION PAIRED WITH COGNITIVE MANIPULATION ACUTELY CHANGES BID IN AN; (2) DETERMINE CROSS-SECTIONAL MULTIMODAL ASSOCIATIONS BETWEEN INTEROCEPTION AND BID IN AN; AND (3) EXPLORE LONGITUDINAL ASSOCIATIONS AND MECHANISTIC MEDIATORS OF BID CHANGE IN AN. THE CURRENT PROJECT WILL USE A RANDOMIZED PARALLEL-GROUP EXPERIMENTAL THERAPEUTIC DESIGN TO EXPLORE A MECHANISTIC FRAMEWORK SUGGESTING DISRUPTED INTEROCEPTIVE PROCESSING PRODUCES DISTURBED BODY IMAGE. THIS PROJECT WILL ADVANCE CURRENT SCIENTIFIC KNOWLEDGE OF THE RELATIONSHIP BETWEEN BID AND INTEROCEPTION AND PAVE THE WAY FOR FUTURE MECHANISTICALLY INFORMED TREATMENT TECHNIQUES FOR BID IN EATING DISORDERS. THE RIGOROUS TRAINING PLAN PROPOSED BY DR. CHOQUETTE INCLUDES FORMAL COURSE WORK, DIDACTICS, AND MENTORSHIP FROM A TEAM OF HIGHLY QUALIFIED MENTORS AND CONSULTANTS. THESE TRAINING ACTIVITIES WILL ALLOW DR. CHOQUETTE TO DEVELOP AN EXPERTISE IN PSYCHOPHYSIOLOGY RESEARCH METHODOLOGY, ADVANCED STATISTICS, AND CONTENT AREA EXPERTISE NEEDED TO PROGRESS TOWARDS INDEPENDENCE AS A CLINICAL SCIENTIST. THE TRAINING LOCATION, LAUREATE INSTITUTE FOR BRAIN RESEARCH (LIBR), IS A STATE-OF-THE-ART RESEARCH INSTITUTION WITH A HISTORY OF SUPPORTING EARLY CAREER SCIENTISTS TRANSITION TO INDEPENDENCE. FURTHER, LIBR IS HOME TO THE FLOAT CLINIC AND RESEARCH LAB AND CO-LOCATED WITH THE LAUREATE EATING DISORDER PROGRAM WHICH WILL FACILITATE COMPLETION OF THE PROPOSED PROJECT. THE CURRENT PROJECT WILL BE THE NEXT LOGICAL AND IMPERATIVE STEP IN DR. CHOQUETTE'S CAREER AND WILL SUPPORT HER PURSUIT OF HER CAREER GOAL OF DEVELOPING MECHANISTICALLY INFORMED TREATMENTS FOR BID IN EATING DISORDERS.

FUNCTIONAL NEUROIMAGING AND TRANSCRANIAL MAGNETIC STIMULATION IN MAL DE DEBARQUEM

DOSE-DEPENDENT FUNCTIONAL CONNECTIVITY EFFECTS OF LOW-INTENSITY FOCUSED ULTRASOUND APPLIED TO DEEP WHITE MATTER TRACTS IN HUMANS - PROJECT ABSTRACT LOW INTENSITY FOCUSED ULTRASOUND (LIFU) IS A NOVEL TECHNIQUE PRODUCING NONINVASIVE, REVERSIBLE, AND ANATOMICALLY PRECISE NEUROMODULATION OF DEEP STRUCTURES IN THE BRAIN. THUS FAR, IT HAS BEEN SUCCESSFULLY EMPLOYED IN HUMANS TO MODULATE THE ACTIVITY OF GRAY MATTER HUBS, INCLUDING AMYGDALA, THALAMUS, AND CEREBRAL CORTEX. BURGEONING IN VITRO DATA SHOWS THAT LIFU IS ALSO A POWERFUL MODULATOR OF AXONAL CONDUCTION, BY OPERATING MECHANOSENSITIVE TRAAK POTASSIUM CHANNELS IN NODES OF RANVIER. IN A RECENTLY COMPLETED PILOT STUDY (NCT 05697172; FDA NON-SIGNIFICANT RISK), WE TRANSLATED THOSE FINDINGS TO HUMAN SUBJECTS BY APPLYING LIFU TO DEEP BRAIN WHITE MATTER TRACTS, REASONING THAT A SUCCESSFUL STUDY WOULD ALLOW THE MODULATION OF LARGE- SCALE BRAIN CIRCUITS AND THUS POTENTIALLY EXPLORE THEIR MECHANISTIC RELATIONSHIP WITH NORMAL AND ABNORMAL BEHAVIOR. SPECIFICALLY, WE OBSERVED THAT A SINGLE SONICATION APPLIED TO TRACTS TRAVERSING THE ANTERIOR LIMB OF THE INTERNAL CAPSULE (ALIC) PRODUCES A FUNCTIONAL DISCONNECTION OF THE CONNECTED GRAY MATTER REGIONS, AS ASSESSED WITH RESTING-STATE FUNCTIONAL MAGNETIC RESONANCE IMAGING (FMRI). NOW WE PROPOSE TO DEFINE THE DOSE- DEPENDENT EFFECTS OF LIFU APPLIED TO WHITE MATTER TRACTS REGARDING BOTH INTENSITY AND DURATION OF ITS NEUROMODULATORY EFFECTS. WE PLAN TO STUDY 60 HEALTHY ADULTS WHO WILL BE RANDOMLY EXPOSED TO TWO DIFFERENT DOSES OF LIFU APPLIED TO TRACTS CONNECTING THE THALAMUS WITH THE SUBGENUAL CINGULATE (SGCC) AND ORBITOFRONTAL (OFC) CORTICES, NAMELY ONE AND THREE LIFU EPOCHS (AS EMPLOYED IN OUR PILOT STUDY: 80 S DURATION; 2.26 WATT/CM2 DERATED TISSUE PEAK PULSE AVERAGE INTENSITY; 10% DUTY CYCLE, 500 KHZ). THE TARGET WHITE MATTER TRACTS WILL BE DEFINED IN EACH INDIVIDUAL PARTICIPANT BY MEANS OF PROBABILISTIC TRACTOGRAPHY. THE AIM 1 OF THIS PROPOSAL IS TO DETERMINE THE RELATIONSHIP BETWEEN LIFU DOSE AND INTENSITY OF TARGET ENGAGEMENT IN TERMS OF DECREASED FMRI FUNCTIONAL CONNECTIVITY BETWEEN THE GRAY MATTER REGIONS CONNECTED BY THE SONICATED WHITE MATTER TRACTS (I.E., THALAMUS AND BOTH SGCC AND OFC). AIM 2 IS TO DETERMINE THE INFLUENCE OF BASELINE STRUCTURAL (NUMBER OF CONNECTING STREAMLINES) AND FUNCTIONAL (FMRI CONNECTIVITY) ON THE DOSE-DEPENDENT LIFU MODULATION EFFECTS. IN AIM 3 WE WILL DETERMINE THE DURATION OF THE NEUROMODULATION EFFECT OF THE TWO DIFFERENT DOSES OF LIFU. A SUCCESSFUL STUDY WILL RESULT IN THE DEFINITION OF DOSE-RESPONSE RELATIONSHIPS BETWEEN WHITE MATTER LIFU MODULATION AND ENGAGEMENT OF THE TARGETED BRAIN CIRCUIT. THIS WILL PAVE THE WAY FOR THE DEVELOPMENT OF MECHANISTIC STUDIES CONSISTENTLY LINKING ABERRANT FUNCTION OF LARGE-SCALE BRAIN CIRCUITS AND BASIC BEHAVIORAL PROCESSES, WITH THE LONG-TERM GOAL OF IMPROVING THE DEFINITION OF PRECISION NEUROMODULATION TARGETS IN TREATMENT-RESISTANT DEPRESSION AND OTHER PSYCHIATRIC DISORDERS.

EO14042 OCEAN COMMUNITY ENGAGEMENT AND AWARENESS USING NASA OBSERVATIONS AND SCIENCE FOR LOW-INCOME HISPANIC/LATINO STUDENTS (OCEANOS)

CYTOMEGALOVIRUS, BRAIN ALTERATIONS, AND DEPRESSION: DECODING NEUROINFLAMMATORY PATHWAYS FOR EFFECTIVE INTERVENTION - PROJECT ABSTRACT/SUMMARY DEPRESSION AFFECTS AT LEAST ONE IN EVERY SIX PEOPLE, AND IDENTIFYING TARGETABLE RISK FACTORS IS URGENTLY NEEDED TO FACILITATE EARLY INTERVENTION AND PREVENTION. THE LITERATURE AND THE APPLICANT'S PILOT STUDIES SUGGESTING THE NEUROTROPIC HERPES VIRUS, SUCH AS CYTOMEGALOVIRUS (CMV) INFECTION, IS CAPABLE OF INDUCING NEUROINFLAMMATION, WHICH HAS BEEN ESTABLISHED AS AN IMPORTANT FACTOR THAT CONTRIBUTES TO THE DEVELOPMENT OF DEPRESSION IN VULNERABLE INDIVIDUALS. THE OBJECTIVE FOR THE PROPOSED K01 AWARD IS TO USE CMV INFECTION AS A MODEL TO DEVELOP A COMPREHENSIVE UNDERSTANDING THAT CMV INFECTION-ASSOCIATED NEUROINFLAMMATORY MECHANISM PREDICTS DISRUPTION OF FRONTOTEMPORAL CIRCUITRY AND INCREASED ODDS OF DEPRESSION. THE APPLICANT WILL USE A MULTIFACETED APPROACH TO UNDERSTAND THE POTENTIAL NEUROBIOLOGICAL PATHWAYS THAT MAY INCREASE THE RISK OF DEPRESSION IN INDIVIDUALS WITH CMV INFECTION. THIS APPROACH INCLUDES THE USE OF EXISTING BLOOD-BASED SEROLOGICAL MARKERS TO DETERMINE CMV SEROSTATUS AND ANTIBODY LEVELS, DIFFUSION-WEIGHTED NEUROIMAGING TO ASSESS BRAIN MICROSTRUCTURE INTEGRITY, POLYGENIC SCORE METHODS TO PROVE HOST ANTI-CMV IMMUNITY, AND BEHAVIORAL ASSESSMENTS TO IDENTIFY DEPRESSION CASES AND MATCHED CONTROLS, AS WELL AS DEPRESSIVE SYMPTOMS, WITHIN THE UK BIOBANK DATASET. THE PROPOSED RESEARCH AIMS TO: (1) DETERMINE THE ASSOCIATIONS BETWEEN CMV SEROPOSITIVITY, BRAIN ALTERATIONS, AND DEPRESSION USING THE LARGEST SEROLOGICAL SAMPLE SO FAR; (2) INVESTIGATE LINKS BETWEEN GENETIC PREDISPOSITION TO CMV SEROPOSITIVITY, BRAIN ALTERATIONS, AND DEPRESSION; AND (3) EXPLORE GENETICALLY PREDICTED INFLAMMATORY MOLECULAR PATHWAYS THROUGH WHICH CMV INFECTION MAY AFFECT BRAIN INTEGRITY AND DEPRESSIVE SYMPTOMS. THIS STUDY WILL EMPLOY RIGOROUS METHODS TO ELUCIDATE THE ROLE OF CMV IN BRAIN ALTERATION AND DEPRESSION, WHICH CAN LEAD TO AN ACTIONABLE TARGET TO MITIGATE NEUROINFLAMMATION AND REDUCE DEPRESSION RISK. THE INNOVATIVE APPROACH LEVERAGES POLYGENIC SCORES TO CAPTURE INDIVIDUAL GENETIC DIFFERENCES IN HOST IMMUNITY, OFFERING AN OPPORTUNITY TO IDENTIFY AT-RISK INDIVIDUALS AND INVESTIGATE THE INFLAMMATORY MECHANISMS INVOLVED. THIS CAREER DEVELOPMENT AWARD BUILDS UPON THE APPLICANT'S NEUROIMAGING EXPERTISE AND PRIOR RESEARCH FOCUS, AND FURTHER PROVIDES TRAINING TO: (1) BRIDGE THE KNOWLEDGE GAP ON VIRAL EPIDEMIOLOGY IN THE CONTEXT OF MENTAL HEALTH; (2) REFINE THE UNDERSTANDING OF THE DISRUPTED BRAIN CIRCUITS AND THEIR RELATIONSHIP WITH THE CLINICAL SYMPTOMS OF INFLAMMATION-ASSOCIATED DEPRESSION; (3) APPLY STATISTICAL GENETICS TO PROBE INDIVIDUAL DIFFERENCES IN IMMUNITY; AND (4) DEVELOP PROFESSIONAL SKILLS AND TRANSITION TO INDEPENDENCE. THE PROPOSED RESEARCH AND TRAINING WILL BE MENTORED BY A TEAM OF LEADING EXPERTS WITH DIVERSE, COMPLEMENTARY EXPERTISE, ENSURING SUCCESSFUL OUTCOMES. UPON COMPLETION OF THIS AWARD, THE APPLICANT WILL BE WELL-PREPARED FOR AN INDEPENDENT RESEARCH CAREER IN POPULATION IMMUNOPSYCHIATRY, FOCUSING TO (1) GAIN A MECHANISTIC UNDERSTANDING OF HOW NEUROTROPIC VIRAL INFECTION MAY CONFER RISK FOR MOOD DISORDERS; AND (2) DETERMINE WHICH SPECIFIC INDIVIDUALS ARE AT RISK FOR DEPRESSION ACROSS THE LIFESPAN AND THE MECHANISMS OF WHY THEY ARE AT RISK.

NEUROSCIENTIFIC EXPLORATION OF CULTURAL PROTECTIVE FACTORS IN AMERICAN INDIANS - PROJECT SUMMARY AMERICAN INDIAN (AI) POPULATIONS HAVE HAD THE LARGEST INCREASE IN SUICIDE RATES OF ANY ETHNIC GROUP IN THAT PAST DECADE AND HAVE HIGH RATES OF MENTAL HEALTH CONCERNS SUCH AS POST-TRAUMATIC STRESS, SUBSTANCE USE, ANXIETY, AND MOOD DISORDERS. HOWEVER, PREVIOUS RESEARCH AND PRELIMINARY ANALYSES DEMONSTRATED THAT AIS ACTUALLY DISPLAY LOWER LEVELS OF MENTAL HEALTH CONCERNS THAN BROADER POPULATIONS WHEN ACCOUNTING FOR INCREASED LEVELS OF RISK FACTORS, (E.G., TRAUMA EXPOSURE). EXTANT LITERATURE INDICATES THAT FACTORS ASSOCIATED WITH AI CULTURE ARE PROTECTIVE AGAINST POOR MENTAL HEALTH. YET, LITTLE IS KNOWN ABOUT HOW CULTURAL FACTORS (E.G., ENCULTURATION, SOCIAL SUPPORT) PLAY A PROTECTIVE ROLE. THERE ARE NO PUBLISHED STUDIES EXAMINING NEURAL UNDERPINNINGS OF THE PROTECTIVE ROLE OF AI CULTURAL FACTORS. FILLING THIS GAP IS A CRITICAL STEP IN SUPPORTING AN EXPERIMENTAL THERAPEUTICS APPROACH TO DEVELOPING CULTURALLY INFORMED PREVENTION AND INTERVENTION EFFORTS. COGNITIVE CONTROL IS A NEUROCOGNITIVE FUNCTION THAT IS IMPLICATED ACROSS NUMEROUS PSYCHIATRIC DISORDERS, CAN BE ASSESSED WITH VALIDATED BEHAVIORAL AND NEUROIMAGING TASKS, AND HAS BEEN WELL-DELINEATED IN REGARD TO UNDERLYING NEURAL CIRCUITRY. THE AIMS OF THE PROPOSAL ARE TO (A) DETERMINE WHETHER CULTURAL PROTECTIVE FACTORS RELATE TO BEHAVIORAL AND NEURAL INDICATORS OF COGNITIVE CONTROL, AS MEASURED DURING ELECTROENCEPHALOGRAPHY AND FUNCTIONAL MAGNETIC RESONANCE IMAGING AND (B) DEVELOP AN EXPERIMENTAL, CULTURAL IDENTIFICATION PARADIGM TO SERVE AS THE BASIS FOR FUTURE CULTURALLY-INFORMED NEUROSCIENTIFIC RESEARCH AND INTERVENTION/PREVENTION EFFORTS. A COMMUNITY BASED PARTICIPATORY RESEARCH (CBPR) FRAMEWORK WILL BE USED TO RECRUIT PARTICIPANTS WHO HAVE COMPLETED MULTIMODAL NEURAL AND BEHAVIORAL INDICATORS OF COGNITIVE CONTROL, CLINICAL INTERVIEWS, SELF-REPORT MEASURES OF PSYCHOPATHOLOGY SYMPTOMS AND GLOBAL FUNCTIONING AS PART OF A PREVIOUS STUDY. THEY WILL COMPLETE SELF-REPORT MEASURES OF ENCULTURATION, SOCIAL SUPPORT, GLOBAL FUNCTIONING AND A CULTURAL ENHANCEMENT INDUCTION PARADIGM DEVELOPED USING A CBPR FRAMEWORK. THESE DATA WILL PROVIDE AN ESSENTIAL FOUNDATION FOR DEVELOPING CULTURALLY INFORMED, EVIDENCE-BASED INTERVENTION AND PREVENTION EFFORTS AIMED AT REDUCING THE MENTAL HEALTH DISPARITIES AMONG AIS. THE PROPOSED TRAINING PLAN WILL EXPAND DR. WHITE EXPERTISE IN NEUROSCIENTIFIC MECHANISMS OF COGNITIVE CONTROL THROUGH MENTORSHIP, COURSEWORK, AND HANDS-ON TRAINING IN ADVANCED STATISTICAL METHODS, MULTIMODAL (EEG/FMRI) NEUROIMAGING, CLINICAL NEUROSCIENCE, AND CULTURALLY INFORMED RESEARCH. HE HAS ASSEMBLED A TEAM OF MENTORS WELL SUITED TO PROVIDE THE REQUIRED DIVERSITY OF EXPERTISE HE NEEDS TO ACHIEVE INDEPENDENCE. DR. MARTIN PAULUS WILL PROVIDE EXPERTISE NEUROIMAGING AND ADVANCED DATA ANALYTIC EXPERTISE. DR. AUPPERLE WILL BRING EXTENSIVE EXPERIENCE RELATED TO NEUROIMAGING AND CLINICALLY RELEVANT NEUROSCIENCE APPROACHES. DR. LOWE WILL PROVIDE EXPERTISE AND EXPERIENCES IN AI CULTURALLY INFORMED RESEARCH. THE TRAINING AND ASSOCIATED RESEARCH WILL BE CONDUCTED AT LIBR, A STATE-OF-THE-ART INSTITUTE DEDICATED TO NEUROIMAGING RESEARCH AIMED AT DEVELOPING MORE EFFECTIVE TREATMENTS FOR NEUROPSYCHIATRIC DISORDERS.

IN VIVO INFLAMMATORY CHALLENGE TO ELUCIDATE THE ROLE OF THE TOLL-LIKE RECEPTOR 4 PATHWAY IN DEPRESSION - PROJECT SUMMARY APPROXIMATELY 1/3 OF INDIVIDUALS WITH MAJOR DEPRESSIVE DISORDER (MDD) DISPLAY INFLAMMATION THAT IS BELIEVED TO PLAY A CAUSAL ROLE IN THE DISORDER, BUT THE PRECISE MECHANISMS ARE NOT UNDERSTOOD. EXPERIMENTAL ENDOTOXEMIA STUDIES IN HEALTHY INDIVIDUALS HAVE SHOWN BEHAVIORAL, IMMUNOLOGICAL, AND PHYSIOLOGICAL CHANGES LEADING TO A TRANSIENT DEPRESSIVE-LIKE STATE THAT RESOLVES 4-5 HOURS AFTER ADMINISTRATION OF LIPOPOLYSACCHARIDE (LPS). WHILE INFORMATIVE, THESE STUDIES CANNOT REVEAL PUTATIVE, ABERRANT INFLAMMATORY AND REGULATORY MECHANISMS IN MDD. HENCE, A MECHANISTIC APPROACH IS REQUIRED TO PINPOINT WHICH IMMUNOREGULATORY MECHANISMS ARE DEFECTIVE IN MDD. THIS PROPOSAL WILL LEVERAGE AN EXPERIMENTAL MEDICINE STUDY INVOLVING ACUTE ADMINISTRATION OF LPS OR SALINE TO INDIVIDUALS WITH MDD AND HEALTHY CONTROLS (HC) TO IDENTIFY DEPRESSION-RELEVANT CHANGES IN THE TLR4 PATHWAY AND ITS REGULATION BY MICRORIBONUCLEIC ACIDS (MIRNAS) IN BOTH THE BLOOD AND THE BRAIN. THE CENTRAL HYPOTHESIS IS THAT TLR4 SIGNALING IS SENSITIZED IN MDD BY A HISTORY OF EXPOSURE TO EXOGENOUS (E.G. PATHOGENS, LPS FROM LEAKY GUT) AND/OR ENDOGENOUS (E.G. CHRONIC STRESS) LIGANDS, AND THUS, TLR4-MEDIATED INFLAMMATORY AND REGULATORY MECHANISMS ARE IMPAIRED IN MDD SUBJECTS COMPARED TO HC. TLR4 DETECTS PATHOGEN- AND DAMAGE-ASSOCIATED MOLECULAR PATTERNS (PAMPS AND DAMPS) FOR PRODUCTION OF INFLAMMATORY CYTOKINES, SUCH AS INTERLEUKIN 6 (IL-6) AND TUMOR NECROSIS FACTOR (TNF), WHICH ARE ELEVATED IN SOME INDIVIDUALS WITH MDD. WHILST PAMPS, LIKE LPS PLAY A ROLE IN THE PATHOGENESIS OF MDD, STRESS-ASSOCIATED PRODUCTION OF DAMPS MAY ALSO ACTIVATE TLR4. DESPITE THE THEORETICAL IMPORTANCE OF THE TLR4 PATHWAY, THE EVIDENCE BASE IS CURRENTLY SMALL, THE EXTANT CLINICAL DATA ARE CROSS-SECTIONALLY DERIVED, AND TLR4 DOWNSTREAM SIGNALING HAS NOT BEEN ASSESSED DESPITE ABERRANT EXPRESSION OF TLR4-RESPONSIVE MIRNAS IN MDD. THESE MIRNAS CAN BE ISOLATED FROM EXTRACELLULAR VESICLES (EVS) THAT CROSS THE BLOOD BRAIN BARRIER, THUS, ISOLATING EVS OF GLIAL ORIGIN WILL PROVIDE A READOUT OF CNS-ASSOCIATED TLR4 REGULATION IN MDD. OUR PRELIMINARY DATA SUGGEST THAT THE INFLAMMATORY CYTOKINES, IL-6 AND TNF, AS WELL AS TLR4 ARE INCREASED IN MDD COMPARED TO HC IN RESPONSE TO LPS. THE K99 PHASE WILL IDENTIFY PERIPHERAL AND CENTRAL TLR4-MEDIATED IMMUNE SIGNALING MECHANISMS IN MDD WITH THE USE OF HIGH-SENSITIVITY, IMMUNOASSAY DETECTION TO IDENTIFY CHANGES IN CYTOKINE EXPRESSION AND TLR4 PATHWAY PROTEINS AND SUPPORT THE PI’S TRAINING IN FLOW CYTOMETRY, MIRNA EXTRACTION, ASTROCYTE-ENRICHED EV (AEEV) ISOLATION, AND RNA-SEQ. THE R00 PHASE WILL IDENTIFY PERIPHERAL AND CENTRAL TLR4-MEDIATED REGULATORY MECHANISMS IN MDD WITH THE USE OF NEXT GENERATION SEQUENCING TO IDENTIFY MIRNAS DYSREGULATED IN MDD AND WILL PROVIDE SUPPORT FOR TRANSITION TO AN INDEPENDENT INVESTIGATOR SPECIALIZING IN CNS-DEPENDENT TLR4- INFLAMMATORY MECHANISMS IN DEPRESSION. THE ABILITY TO DELINEATE TLR4-MEDIATED PERIPHERAL AND CNS IMMUNOREGULATORY RESPONSES WITH CUTTING EDGE TECHNIQUES, STILL NOVEL TO THE FIELD OF PSYCHIATRY, WILL MOVE US ONE STEP CLOSER TO UNDERSTANDING THE MECHANISMS UNDERLYING INFLAMMATION-ASSOCIATED DEPRESSION.

SOFTWARE TO ENRICH THE NOUN LEXICONS AND LEXICAL LEARNING OF CHILDREN WITH AUTISM

EFFECTS OF AMYGDALA NEUROFEEDBACK ON DEPRESSIVE SYMPTOMS AND PROCESSING BIASES